Proper function of the epithelial lining the gastrointestinal (GI) tract depends upon tight regulation of a number of cellular and biochemical events that organize complex signal transduction pathways. An important question regarding the continuous and rapid renewal of this tissue, normally and following injury is how decisions about cell proliferation, migration and death are made and how aberrant processing of these decisions results in disease from ulceration to tumorigenesis. Tumor necrosis factor (TNF) receptor (R) family members are important in regulation of growth, migration, differentiation and apoptosis of a number of cells and tissues. Studies from our laboratory and others indicate these proteins play key regulatory roles in intestinal development and homeostasis. Their expression, activation or signal transduction pathways are altered in a number of gastrointestinal disorders including inflammatory bowel diseases, celiac disease, Helicobacter pylori gastritis, necrotizing enterocolitis and non-steroidal anti-inflammatory drug-induced gastrointestinal diseases. In the current proposal we will extend our previous findings under the initial funding of this program using state-of-the art molecular, genetic and proteomic approaches in cell culture and mouse models to further test our hypothesis that TNFR family members determine intestinal homeostasis by mediating opposing TNF-induced responses on epithelial cell proliferation, migration, differentiation and apoptosis. Therefore, our Specific Aims are to: 1. determine the signal transduction pathways initiated by TNFR1 regulating intestinal cell growth inhibition, survival and migration, 2. identify and characterize downstream targets of TNFR2 activation that promote epithelial cell growth and migration and 3. determine the role of TNFRs in regulating in vivo intestinal epithelial response to TNF, injury and repair. The proposed studies will significantly enhance our understanding of the roles and mechanisms of action for TNFRs effects on intestinal epithelial health with implications for a number of human gastrointestinal disorders.